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The Two-pore channel (TPC) interactome unmasks isoform-specific roles for TPCs in endolysosomal morphology and cell pigmentation. Proc Natl Acad Sci U S A 2014 Sep 09;111(36):13087-92



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Scopus ID

2-s2.0-84907001175   61 Citations


The two-pore channels (TPC1 and TPC2) belong to an ancient family of intracellular ion channels expressed in the endolysosomal system. Little is known about how regulatory inputs converge to modulate TPC activity, and proposed activation mechanisms are controversial. Here, we compiled a proteomic characterization of the human TPC interactome, which revealed that TPCs complex with many proteins involved in Ca(2+) homeostasis, trafficking, and membrane organization. Among these interactors, TPCs were resolved to scaffold Rab GTPases and regulate endomembrane dynamics in an isoform-specific manner. TPC2, but not TPC1, caused a proliferation of endolysosomal structures, dysregulating intracellular trafficking, and cellular pigmentation. These outcomes required both TPC2 and Rab activity, as well as their interactivity, because TPC2 mutants that were inactive, or rerouted away from their endogenous expression locale, or deficient in Rab binding, failed to replicate these outcomes. Nicotinic acid adenine dinucleotide phosphate (NAADP)-evoked Ca(2+) release was also impaired using either a Rab binding-defective TPC2 mutant or a Rab inhibitor. These data suggest a fundamental role for the ancient TPC complex in trafficking that holds relevance for lysosomal proliferative scenarios observed in disease.

Author List

Lin-Moshier Y, Keebler MV, Hooper R, Boulware MJ, Liu X, Churamani D, Abood ME, Walseth TF, Brailoiu E, Patel S, Marchant JS


Jonathan S. Marchant PhD Chair, Professor in the Cell Biology, Neurobiology and Anatomy department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Calcium Channels
Calcium Signaling
Cell Proliferation
Chromatography, Affinity
HEK293 Cells
Protein Binding
Protein Isoforms
Reproducibility of Results
rab GTP-Binding Proteins
jenkins-FCD Prod-482 91ad8a360b6da540234915ea01ff80e38bfdb40a